Obesity increases cytokine levels and generates a state of chronic oxidative stress that may facilitate prostate tissue inflammation. Several prior prospective studies report obesity is associated with clinical symptoms of benign prostatic hyperplasia (BPH). However, the relationship between obesity and prostate tissue inflammation remains unclear, and the relevance of obesity-induced inflammation and oxidative stress is undetermined. Our goal is first to determine if obesity (BMI, waist circumference, waist-hip ratio, % body fat from bioelectric impedance analysis) is associated with inflammatory leukocyte cell count and inflammation severity in prostate biopsy cores from 500 men without prostate cancer or prostatic intraepithelial neoplasia. We will also investigate the association between prostate inflammation and four promising and validated biomarkers of inflammation and oxidative stress (urine prostaglandin E2 (PGE-M) and F2-isoprostane (F2iP-M) metabolites), and blood adiponectin and C-reactive protein (CRP) levels, that may mediate the effects of obesity on BPH progression. We will also characterize the mechanisms by which obesity and NF-kB activity induce the development of prostate hyperplasia in two mouse models of obesity (ob/ob and agouti). To describe the clinical impact of obesity on BPH progression, we will then prospectively follow study participants for changes in lower urinary tract symptoms and initiation of BPH treatment. Using multivariable linear, logistic, and COX regression, we will describe the associations between obesity, adiponectin, PGE-M, CRP, and F2iP-M levels with indices of prostate tissue inflammation and changes in symptom severity and BPH progression. Our approach is novel, multi-disciplinary, and translational; and will more rapidly lead to new insights into the etiologic and clinical roles of obesity in prostate tissue inflammation and BPH progression. Results may argue for one of several plausible interventions targeting obesity, inflammation, or oxidative stress to delay BPH progression. PUBLIC HEALTH RELEVANCE: This proposal includes a prospective epidemiologic study investigating the relationships between biomarkers of obesity and inflammation on BPH progression. It also investigates the mechanisms linking obesity on prostate hyperplasia utilizing two mouse models of obesity. This multidisciplinary project will advance our understanding of obesity as a risk factor for BPH and will lead to interventions to delay BPH progression by targeting obesity and inflammation pathways.